Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Abstract

Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

Key European guidelines for the diagnosis and management of patients with phenylketonuria

“…РОССИЙСКИЙ ВЕСТНИК ПЕРИНАТОЛОГИИ И ПЕДИАТРИИ, 2017; 62: (5) ROSSIYSKIY VESTNIK PERINATOLOGII I PEDIATRII, 2017; 62: (5) ного регистра лиц, страдающих редкими заболевани-ями, на 01.01.2015 г. -2,51 на 100 000 населения, доля детей -85,3% [2].…”

“…Характер мутации определяет степень остаточной активности фермента или ее отсутствие и в большин-стве случаев коррелирует с тяжестью болезни. Тем не менее корреляция между генотипом и фенотипом у больных не является абсолютной и пациенты с ана-логичными генотипами в некоторых случаях могут иметь различные формы фенилкетонурии [4,5].…”

“…Например, при содержании фенилаланина в крови около 15 мг/дл активность тирозингидрок-силазы подавляется на 80%. Еще одним механизмом повреждения мозга считается снижение активности пируваткиназы, 3-гидрокси-3-метилглутарил-ко-энзим А редуктазы, нарушение глутаматергической передачи нервного импульса и функции моноами-ноксидазы В [1,5,9].…”

Medical genetics and genomic medicine in the United States. Part 2: Reproductive genetics, newborn screening, genetic counseling, training, and registries

“…In each case, they have data showing the response rate to a cofactor treatment that is effective in some patients with PKU (sapropterin dihydrochloride, an isomer of tetrahydrobiopterin). The current guidelines suggest that all PKU patients should have a trial with the cofactor, except those with two truncating mutations in trans (Vockley et al., 2014). The next decades will continue to show how the culture of genetics will create precision medicine for many diseases, metabolic, and chromosomal.…”

Results of a Prospective Study Concerning the Clinical Efficiency of Recent Russian-Made Specialized Foods without Phenylalanine

“…Врач назначает их дополнительно в виде отдельных медикаментозных препаратов или добавок [8]. Одной из проблем диетического лечения больных фенил-кетонурией является высокий риск развития дефицитных состояний, отрицательно сказывающийся на физическом и нервно-психическом развитии больных детей, даже при поддержании низкого уровня фенилаланина в крови [9].…”